Stories of progress, inspiration, and information in overcoming osteosarcoma.

Why Does Osteosarcoma Metastasize?

James Morrow, MD, PhD, is working to understand why osteosarcoma spreads — and how to stop it.

Cancer is more difficult to treat once it has metastasized or spread beyond its original location. Metastatic osteosarcoma in particular, which accounts for about 20% of osteosarcoma diagnoses, is especially challenging to treat, since the disease often spreads to the lungs. Researcher and oncologist James Morrow, MD, PhD, is on a mission to change how metastatic osteosarcoma is treated so patients will survive.

While completing graduate studies at Case Western Reserve University, Dr. Morrow was awarded a 2011–2012 Howard Hughes Medical Institute fellowship, allowing him to study tumor metastasis in the lab of Chand Khanna, DVM, PhD. (Dr. Khanna serves as Strategic Advisory Board Chair at the Osteosarcoma Institute.)

Building on this research, Dr. Morrow joined the lab of Peter Scacheri, PhD, at Case Western and published a 2018 study in Nature Medicine describing the role that gene enhancers play in tumor metastasis. Today, as a clinical fellow at Dana-Farber Cancer Institute in Boston, Dr. Morrow splits his time between his osteosarcoma research and treating young patients in the clinic. The Frontline sat down with Dr. Morrow to learn more about what is on the horizon for treating metastatic osteosarcoma.

Can you explain what metastasis is and what role it plays in osteosarcoma?

Metastasis is the process by which cancer cells that are initially in primary tumors leave those tumors and spread to other parts of the body. Cancer in general, and osteosarcoma in particular, is much more difficult to treat once it has metastasized.

The statistics are sobering. Patients who present with metastatic disease do not achieve cures about 70% of the time, whereas patients who present without metastatic disease do achieve cures about 70% of the time. My work treating patients serves as a critical motivator for my research, because I see firsthand the impact that new approaches to treatment can have for individual patients and their families.

Can you share your research involving gene enhancers and how they are connected to metastasis?

Think of gene enhancers as switches that turn on or dial up gene expression. They are not genes themselves, but they are the key drivers of cell identity. In any given cell type, there could be tens of thousands or hundreds of thousands of gene enhancers that form a sort of circuitry in the cell.

“We found there is a broad rewiring or reprogramming of the cell that occurs as osteosarcoma gains the ability to metastasize, and that turns out to be a key driver of that ability.” — James Morrow, MD, PhD

My research has studied the enhancers’ role in osteosarcoma metastasis. We found there is a broad rewiring or reprogramming of the cell that occurs as osteosarcoma gains the ability to metastasize, and that turns out to be a key driver of that ability.

What were some of the differences that you saw in the enhancers in metastatic cells versus non-metastatic ones?

When we took a 10,000-foot view at the differences in the enhancer landscape in a non-metastatic osteosarcoma cell and a metastatic osteosarcoma cell, we saw that there were many changes in the genome of a metastatic osteosarcoma cell that ultimately change the genes that cell expresses.

Looking more systematically, we found that there were specific, non-random areas with gained enhancer activity and lost enhancer activity. Those changes seemed to center on particular genes.
We looked at genes in metastatic cells where we saw a lot of increased enhancer activity and we asked, “If we alter the function of that gene, or we knock the gene down, can we limit the osteosarcoma cell’s ability to metastasize?” The answer we found was yes. Not only are these changes happening in a selective way, but they are functionally critical to that cell’s ability to metastasize.

Ultimately, how will this research benefit osteosarcoma patients?

Since the presence of metastasis tells us how difficult it is going to be to treat an individual patient’s osteosarcoma, if we can really understand the biology of metastasis, we can find creative ways to treat it. We know that standard chemotherapy does not do a great job of treating metastatic osteosarcoma. We hope that what we learned about the biology of metastasis from this work will open avenues for the development of novel treatment strategies. In fact, some of that translational work is ongoing now.

How does funding play a role in making your research possible?

As pediatric oncologists and scientists who study pediatric cancers, we are in the unfortunate situation of having a much smaller pool of funding than folks who are studying adult cancers. Part of the reason for that is that, thankfully, these types of cancers are less common than adult tumors, but that does not make pediatric oncology any less important.

Because funding for studying pediatric cancers like osteosarcoma is not as widely available, funding mechanisms like that of the Osteosarcoma Institute are critical to driving this work forward. Particularly in the early phases, philanthropic funding is the fuel that drives discovery that then can go on to lead to new therapeutic advances.